Substituted phenylalkenoylguanidines, process for their preparation, and their use in medicaments and in diagnostics

Abstract

Substituted phenylalkenoylguanidines, processes for their preparation, uses as medicaments or diagnostics, and medicaments containing them are described. The invention relates to substituted phenylalkenoylguanidines and their pharmaceutically tolerable salts and physiologically functional derivatives of the formula ##STR1## in which the radicals have the meanings indicated, and their physiologically tolerable salts and processes for their preparation. The compounds are suitable as medicaments for the prophylaxis or treatment of gallstones.

We claim: 
     
       1. A compound described by formula I ##STR25## wherein one of T1 and T2 is ##STR26##  and the other one of T1 and T2 is hydrogen or each of T1 and T2 is ##STR27## R(A), R(B), R(C), R(D) independently of one another are selected from the group consisting of hydrogen, F, Cl, Br, I, CN, OH, NH 2 , --(C 1  -C 8 )-alkyl, and --O--(C 1  -C 8 )-alkyl, wherein each alkyl radical is unsubstituted or is substituted at least once with a substituent selected from the group consisting of F; (C 3  -C 8 )-cycloalkyl, phenyl, benzyl, NHR(7), NR(7)R(8), O--(C 3  -C 6 )-alkenyl, O--(C 3  -C 8 )-cycloalkyl, O-phenyl, and O-benzyl, wherein the phenyl nucleus is unsubstituted or is substituted 1 to 3 times by a substituent selected from the group consisting of F, Cl, CF 3 , methyl, methoxy, and NR(9)R(10); R(7), R(8) independently of one another are selected from the group consisting of hydrogen, --(C 1  -C 8 )-alkyl, and a chain of 4 or 5 methylene groups formed from both R(7) and R(8) wherein one CH 2  group is not replaced or replaced by oxygen, sulfur, NH, N--CH 3  or N-benzyl, and wherein the alkyl radical is unsubstituted or is substituted at least once by a substituent selected from the group consisting of F, (C 3  -C 8 )-cycloalkyl, (C 3  -C 6 )-alkenyl, (C 3  -C 8 )-cycloalkyl, phenyl, and benzyl, wherein the phenyl nucleus is unsubstituted or is substituted 1 to 3 times by a substituent selected from the group consisting of F, Cl, CF 3 , methyl, methoxy, and NR(9)R(10);   R(9), R(10) independently of one another are selected from the group consisting of hydrogen, (C 1  -C 4 )-alkyl, and (C 1  -C 4 )-perfluoroalkyl;   x is zero, 1 or 2;   y is zero, 1 or 2;   R(E), R(F) independently of one another are selected from the group consisting of hydrogen, F, Cl, Br, I, CN, (C 1  -C 8 )-alkyl, and O--(C 1  -C 8 )-alkyl, wherein each alkyl radical is unsubstituted or is substituted at least once by a substituent selected from the group consisting of F, (C 3  -C 8 )-cycloalkyl, O--(C 3  -C 6 )-alkenyl, O--(C 3  -C 8 )-cycloalkyl, O-phenyl, and O-benzyl, wherein the phenyl nucleus is unsubstituted or is substituted 1 to 3 times by a substituent selected from the group consisting of F, Cl, CF 3 , methyl, methoxy, and NR(9)R(10);   R(1), R(2), R(3) independently of one another are selected from the group consisting of hydrogen, F, Cl, Br, I, CN, --(C 1  -C 8 )-alkyl, and --O--(C 1  -C 8 )-alkyl, wherein each alkyl radical is unsubstituted or is substituted at least once by a substituent selected from the group consisting of F, --(C═O)--N═C(NH 2 ) 2 , --(SO 0-2 )--(C 1  -C 8 )-alkyl, --(SO 2 )--NR(7)R(), --O--(C 0  -C 8 )-alkylenephenyl, and --(C 0  -C 8 )-alkylenephenyl, wherein each phenyl nuclei is unsubstituted or is substituted 1 to 3 times by a substituent selected from the group consisting of F, Cl, CF 3 , methyl, methoxy, and --(C 0  -C 8 )-alkylene-NR(9)R(10);   L is --O--, --NR(47)-, --(C 1  -C 8 )-alkylene-, --(C 1  -C 8 )-alkenylene-, --(C 1  -C 8 )-alkynylene-, --COO--, --CO--NR(47)-, --SO 2  --NR(47)-, --O--(CH 2 ) n  --O--, --NR(47)-(CH 2 ) n  --O--, --NR(48)-CO--(CH 2 ) n  --O--, --CO--NR(48)-(CH 2 ) n  --O--, --O--CO--(CH 2 ) n  --O--, --SO 2  --NR(48)-(CH 2 ) n  --O--, --NR(48)-CO--CH 2  --CH 2  --CO--NR(48)-(CH 2 ) n  --O--, --NR(48)-CO--CH═CH--CO--NR(48)-(CH 2 ) n  --O--, or --NR(48)-SO 2  --(CH 2 ) n  --O--;   R(47) is hydrogen, (C 1  -C 8 )-alkyl, R(48)-CO--, phenyl, or benzyl;   R(48) is hydrogen, (C 1  -C 8 )-alkyl, phenyl or benzyl, wherein the phenyl nucleus is unsubstituted or is substituted 1 to 3 times by a substituent selected from the group consisting of F, Cl, CF 3 , methyl, and methoxy;   n is 1, 2, 3, 4, 5, 6, 7, or 8;   R(40) to R(45) independently of one another are selected from the group consisting of hydrogen, --OR(50), --SR(50), NHR(50), --NR(50) 2 , --O--(CO)--R(50), --S--(CO)--R(50), --NH--(CO)--R(50), --O--PO--(OR(50))--OR(50), --O--(SO 2 )--OR(50), --R(50) and a bond to L; or   R(40) and R(41), R(42) and R(43), R(44) and R(45) in each case together form an oxygen of a carbonyl group, and wherein only one of the radicals R(40) to R(45) forms a bond with L;   K is --OR(50), --NHR(50), --NR(50) 2 , --HN--CH 2  --CH 2  --CO 2  H, --HN--CH 2  --CH 2  --SO 3  H, --NH--CH 2  --COOH, --N(CH 3 )CH 2  CO 2  H, --HN--CH(R46)CO 2  H, or --OKa, wherein Ka is an ion selected from the group consisting of a cation, an alkali metal cation, an alkaline earth metal cation and a quaternary ammonium ion;   R(46) is (C 1  -C 4 )-alkyl, benzyl, --CH 2  --OH, H 3  CSCH 2  CH 2  --, HO 2  CCH 2 , or HO 2  CCH 2  CH 2  --;   R(50) is hydrogen, (C 1  -C 4 )-alkyl, phenyl or benzyl, wherein the phenyl nucleus is unsubstituted or is substituted 1 to 3 times by a substituent selected from the group consisting of F, Cl, CF 3 , methyl, and methoxy; a pharmaceutically tolerable salt of the compound of formula I.     
     
     
       2. A compound as described in claim 1, wherein one of T1 and T2 is ##STR28## and the other one of T1 and T2 is hydrogen or each of T1 and T2 is ##STR29## R(E) is hydrogen, F, Cl, CN, (C 1  -C 4 )-alkyl, or --O--(C 1  -C 4 )-alkyl, wherein the alkyl radical is unsubstituted or is substituted at least once by a substituent selected from the group consisting of F, (C 3  -C 6 )-cycloalkyl, (C 3  -C 8 )-alkenyl, O--(C 3  -C 6 )-cycloalkyl, O-phenyl, and O-benzyl, wherein the phenyl nucleus is unsubstituted or is substituted 1 to 3 times by a substituent selected from the group consisting of F, Cl, CF 3 , methyl, methoxy, and NR(9)R(10); R(9), R(10) are selected from the group consisting of hydrogen, CH 3 , and CF 3  ;   R(1), R(2), R(3) are selected from the group consisting of hydrogen, F, Cl, CN, --SO 2  --(C 1  -C 4 )-alkyl, --SO 2  --N((C 1  -C 4 )-alkyl) 2 , --SO 2  --NH(C 1  -C 4 )-alkyl, --SO 2  --NH 2 , --SO 2  --(C 1  -C 4 )-alkyl, --(C 1  -C 4 )-alkyl, and --O--(C 1  -C 4 )-alkyl, wherein each alkyl radical is unsubstituted or is substituted at least once by a substituent selected from the group consisting of F, --O--(C 0  -C 4 )-alkylenephenyl, and --(C 0  -C 4 )-alkylenephenyl, wherein the phenyl nucleus is unsubstituted or is substituted 1 to 3 times by a substituent selected from the group consisting of F, Cl, CF 3 , methyl, and methoxy;   L is --O--, --NR(47)-, --(C 1  -C 4 )-alkylene-, --(C 1  -C 4 )-alkenylene-, --(C 1  -C 4 )-alkynylene-, --COO--, --CO--NR(47)-, --SO 2  --NR(47)-, --O--(CH 2 ) n  --O--, --NR(47)-(CH 2 ) n  --O--, --NR(48)-CO--(CH 2 ) n  --O--, --CO--NR(48)-(CH 2 ) n  --O--, or --SO 2  --NR(48)-(CH 2 ) n  --O--;   R(47) is hydrogen, (C 1  -C 4 )-alkyl, R(48)-CO--, or phenyl, benzyl;   R(48) is hydrogen, (C 1  -C 4 )-alkyl, phenyl or benzyl, wherein the phenyl nucleus is unsubstituted or is substituted 1 to 3 times by a substituent selected from the group consisting of F, Cl, CF 3 , methyl, and methoxy;   n is between 1 and 4;   R(41), R(42), R(45) independently of one another are selected from the group consisting of hydrogen, --OR(50), NHR(50), --NR(50) 2 , --O--(CO)--R(50), and --NH--(CO)--R(50);   R(50) is hydrogen, (C 1  -C 4 )-alkyl, phenyl or benzyl, wherein the phenyl nucleus is unsubstituted or is substituted 1 to 3 times by a substituent selected from the group consisting of F, Cl, CF 3 , methyl, and methoxy;   K is --OR(50), --NHR(50), --NR(50) 2 , --HN--CH 2  --CH 2  --CO 2  H, --HN--CH 2  --CH 2  --SO 3  H, --NH--CH 2  --COOH, --N(CH 3 )CH 2  CO 2  H, or --OKa, wherein Ka is an selected from the group consisting of a cation, an alkali metal ion, an alkaline earth metal ion and a quaternary ammonium ion; a pharmaceutically tolerable salt of the compound of formula I.     
     
     
       3. A compound as described in claim 1, wherein one of T1 and T2 is ##STR30##  and the other one of T1 or T2 is hydrogen or each of T1 and T2 is ##STR31## R(E) is hydrogen, F, Cl, CN, (C 1  -C 4 )-alkyl, (C 1  -C 4 )-alkyl, --O(C 1  -C 4 )-alkyl, CF 3 , or --OCF 3  ;   R(1), R(2) independently of one another are selected from the group consisting of hydrogen, F, Cl, CN, --SO 2  --CH 3 , SO 2  NH 2  --, --(C 1  -C 4 )-alkyl, and --O--(C 1  -C 4 )-alkyl, wherein each alkyl radical is unsubstituted or is substituted at least once by F; --O--(C 0  -C 4 )-alkylenephenyl, or --(C 0  -C 4 )-alkylenephenyl, wherein each phenyl nucleus is unsubstituted or is substituted 1 to 3 times by a substituent selected from the group consisting of F, Cl, CF 3 , methyl, and methoxy;   R(3) is hydrogen;   L is --O--, --NR(47)-, --CH 2  --CH 2  --, CH═CH--, --(C.tbd.C)--, --COO--, --CO--NR(47)-, --SO 2  --NR(47)-, --O--(CH 2 ) n  --O--, --NR(47)-(CH 2 ) n-  --O--, --NR(48)-CO--(CH 2 ) n  --O--, --CO--NR(48)-(CH 2 ) n  --O--, or --SO 2  --NR(48)-(CH 2 ) n  --O--;   R(47) is hydrogen, (C 1  -C 4 )-alkyl, R(48)-CO--, phenyl, or benzyl;   R(48) is hydrogen, (C 1  -C 4 )-alkyl, phenyl or benzyl, wherein the phenyl nucleus is unsubstituted or is substituted 1 to 3 times by a substituent selected from the group consisting of F, Cl, CF 3 , methyl, and methoxy;   n is between 1 and 4;   R(41) is hydrogen, or --OH;   K is --OR(50), --NHR(50), --NR(50) 2 , --HN--CH 2  --CH 2  --CO 2  H, --HN--CH 2  --CH 2  --SO 3  H, --NH--CH 2  --COOH, --N(CH 3 )CH 2  CO 2  H, --OKa, where Ka is a cation;   R(50) is hydrogen, (C 1  -C 4 )-alkyl, phenyl or benzyl, where the phenyl nucleus is unsubstituted or substituted 1 to 3 times by F, Cl, CF 3 , methyl, methoxy; or its pharmaceutically tolerable salts.     
     
     
       4. A compound as described in claim 1, wherein the compound further is described by formula Ia. ##STR32## wherein R3 is H; one of T1 and T2 is ##STR33##  and the other one of T1 and T2 is hydrogen or each of T1 and T2 is ##STR34## R(E) is hydrogen, or (C 1  -C 4 )-alkyl; R(1), R(2) independently of one another are selected from the group consisting of hydrogen, F, Cl, CN, --SO 2  --CH 3 , --(C 1  -C 4 )-alkyl, and --O--(C 1  -C 4 )-alkyl, wherein each alkyl radical is unsubstituted or is substituted at least once by F; or a pharmaceutically tolerable salt thereof.     
     
     
       5. A pharmaceutical composition comprising at least one compound as described in claim 1 and an excipient. 
     
     
       6. A pharmaceutical composition as claimed in claim 5 further comprising at least one additional lipid-lowering active compound. 
     
     
       7. A method for the prophylaxis or treatment of gallstones comprising administering a composition that comprises a compound as claimed in claim 1 to a patient in need thereof. 
     
     
       8. A method as described in claim 7 wherein the composition further comprises at least one additional lipid-lowering active compound. 
     
     
       9. A process for the production of a pharmaceutical composition that comprises at least one compound as described in claim 1, comprising the step of mixing the compound with a pharmaceutically suitable excipient in a form suitable for administration to a patient. 
     
     
       10. A pharmaceutical composition comprising at least one compound as described in claim 2 and an excipient. 
     
     
       11. A pharmaceutical composition as claimed in claim 10 further comprising at least one additional lipid-lowering active compound. 
     
     
       12. A method for the prophylaxis or treatment of gallstones comprising administering a composition that comprises a compound as claimed in claim 2 to a patient in need thereof. 
     
     
       13. A process for the production of a pharmaceutical composition that comprises at least one compound as described in claim 2, comprising the step of mixing the compound with a pharmaceutically suitable excipient in a form suitable for administration to a patient. 
     
     
       14. A pharmaceutical composition comprising at least one compound as described in claim 3 and an excipient. 
     
     
       15. A pharmaceutical composition as claimed in claim 14 further comprising at least one additional lipid-lowering active compound. 
     
     
       16. A method for the prophylaxis or treatment of gallstones comprising administering a composition that comprises a compound as claimed in claim 3 to a patient in need thereof. 
     
     
       17. A process for the production of a pharmaceutical composition that comprises at least one compound as described in claim 3, comprising the step of mixing the compound with a pharmaceutically suitable excipient in a form suitable for administration to a patient. 
     
     
       18. A pharmaceutical composition comprising at least one compound as described in claim 4 and an excipient. 
     
     
       19. A pharmaceutical composition as claimed in claim 18 further comprising at least one additional lipid-lowering active compound. 
     
     
       20. A method for the prophylaxis or treatment of gallstones comprising administering a composition that comprises a compound as claimed in claim 4 to a patient in need thereof.